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 Impaired SF, particularly decreases in desire and arousal, has been reported in over 50% of untreated men and women with depression (1,2,3). Antidepressant medications may also interfere with SF, often resulting in orgasmic or ejaculatory difficulties (4,5,6). This can lead to patient dissatisfaction as well as decreased compliance with treatment (7). Men and women with depression may also experience these effects differently. For example, Montejo and others found that men reported a higher frequency, while women reported greater severity, of sexual dysfunction (8). There is also evidence that men report more orgasmic impairment than women during SSRI treatment (9,10) and are less likely to report improved SF over the course of treatment (11). A direct relation between antidepressant response and improved SF has also been reported in women, but not in men (5). The Sex FX was developed as a brief comprehensive scale that applied equally to men and women (figure 1). It has been evaluated in drug-free, depressed, (2) and nonclinical populations (12). In general, women reported lower scores on individual subscales (Drive–Desire, Arousal, Orgasm– Ejaculation) and overall satisfaction, compared with men. This scale also discriminated between drugs during antidepressant treatments (5,13). Since the scale has not been previously compared with other measures of sexual dysfunction, we selected the IRSD-F because of its face validity with DSM-IV criteria for sexual dysfunctions and its use in previous trials (10,14) involving various SSRIs and bupropion. Although pharmacologically unrelated to other antidepressants, bupropion SR has demonstrated efficacy comparable to SSRIs (15) and is generally considered to have a low incidence of drug-induced sexual dysfunction (4). This double-blind comparator trial was conducted to assess the relative effects of bupropion and an SSRI on SF, efficacy, and safety. We selected paroxetine as the active comparator because of its wide spread use and broad range of indications across mood and anxiety disorders. The objectives of this study were threefold. The primary objective was to evaluate SF separately in men and women with depression who met criteria for MDD—current MDE before and during treatment with bupropion SR or paroxetine. The secondary objectives were to compare the Sex FX with the IRSD-F, and to compare antidepressant outcomes with an examination of the relation between level of depression and SF over time. The study was not designed with adequate power to detect significant differences in antidepressant effectiveness between the 2 antidepressants. We hypothesized that there would be differences between reported SF in men and women prior to antidepressant treatment and that paroxetine, but not bupropion, would adversely affect SF in both men and women during antidepressant treatment with a significant correlation between the 2 SF scales overtime. We further hypothesized that both antidepressant agents would demonstrate significant reductions in severity of depression and that there would be a direct relation between antidepressant response and SF in women but not in men. MethodPatient Population Subjects were outpatients between age 18 and 65 years who currently met DSM-IV criteria for MDD—current MDE of at least 4 weeks duration. They were also required to have a minimum score of 18 on the HDRS17 (16), to be in good physical health, to report sexual interest and activity within the past month, and to be willing to complete the assessments and questionnaires over the course of several clinical visits. In addition, they were required to be free of any antidepressant use for a minimum of 2 weeks (4 weeks for fluoxetine) before initiating treatment with either study medication. Concomitant treatment with psychoactive medication, whether prescription or over the counter, was not permitted, except for the hypnotic zopiclone (up to 7.5 mg at night) during the first 2 weeks. Women of child-bearing age were also required to have a negative pregnancy test and to use an acceptable contraceptive method. Exclusion criteria included serious suicide risk (> 3 on the HDRS17 “suicide” item), more than 2 failed trials of antidepressant medications at adequate dose and duration during the current episode, drug abuse or dependence within the past 12 months, and a history of bipolar disorder, psychotic disorder, or organic disorder. We obtained research ethics board approval at each participating site as well as written informed consent from each patient prior to study enrolment. Study Design Patients from 15 sites across Canada were randomly assigned to a double-blind, flexible-dosage trial of bupropion SR (150 to 300 mg daily) or paroxetine (20 to 40 mg daily). They were assessed at 5 study visits, each separated by 2 weeks, over an 8-week period. There was an option to increase the dosage of either medication at Week 4 or Week 6, at the discretion of the treating psychiatrist, up to 300 mg daily for bupropion SR (maximum recommended dosage in Canada) (17) or 40 mg daily for paroxetine. Measures SF was assessed using the Sex FX scale, a brief 13-item clinician-rated interview that takes approximately 5 minutes to administer and evaluates the frequency of desire, arousal, orgasm, and overall satisfaction during the preceding 2 weeks in men and women. The 3 subscales of SF (Desire, 4-items; Arousal, 4-items; Orgasm, 3-items) are rated on a 5-point ordered-frequency scale. Reverse scoring is applied to some items. The sum of scores on these 3 subscales provides a total functioning score. Overall Satisfaction, which is a separate dimension, comprised 2 items, each scored between 0 and 10. Higher scores are associated with better levels of SF or overall satisfaction. SF was also assessed with the IRSD-F assessment, a clinician administered interview developed to confirm the presence or absence, according to DSM-IV criteria, of sexual desire disorder, sexual arousal disorder, and orgasm delay or failure. It also assesses overall satisfaction with SF, with 1 representing very satisfied and 6 representing dissatisfied. A total score was obtained by adding each of these 4 subscales. Higher scores are associated with reduced quality of SF. Depression severity was rated with the HDRS17 by psychiatrists who achieved interrater reliability across sites. Response was defined as a reduction of at least 50% from baseline to endpoint, and remission was defined as a score of 7 or less on the HDRS17. Statistical Analysis We performed statistical analysis using the LOCF method on all subjects who took at least one dose of medication and completed at least a second visit. We used a 1-way ANOVA to examine between-group and sex differences at baseline for HDRS17 and Sex FX scales. To evaluate the changes over time in the Sex FX ad the HDRS17, we performed an MMRM (18) ANOVA, controlling for random and nonrandom effects at baseline and prospectively. We examined mean change from baseline to endpoint using within-subject paired t tests. Pearson chi-square tests were used to compare response and remission rates. All tests of statistical significance were performed at a 2-sided alpha level of 0.05. We performed Pearson correlations to examine the relation between the Sex FX total and overall satisfaction scores with the IRSD-F, separately for men and women. The relation between Sex FX and the HDRS17 over time was also evaluated separately by sex using the Pearson correlation statistic. According to the Bonferroni correction to control for type 1 error, a P value of less than P < 0.001 was required for statistical significance. ResultsDemographic and Clinical Characteristics A total of 141 patients were enrolled; 68 were women (48%) and 73 were men (52%). The mean age was 37.8 (SD 10.5) years. Prior to a second visit, 10 patients (5 women and 5 men) dropped out and are not included in outcome analyses. During the remainder of the trial, 21 patients (8 on bupropion SR and 13 on paroxetine) dropped out between Week 2 and Week 8. There were no statistically significant baseline differences between treatment groups with respect to demographics, dropout rates, or severity of depression. The dosage of bupropion SR was increased to 300 mg daily in 38 (29%) patients. In the paroxetine group, 25 (19%) patients received an increase to 40 mg. The mean dosage for bupropion was 178.5 mg daily. The mean dosage for the paroxetine group was 23.3 mg daily. Differences in SF Between Men and Women Prior to treatment, there were statistically significant differences between men and women on Sex FX total, Desire, Arousal, Orgasm, and overall satisfaction scores (P < 0.001). A one-way ANOVA yielded a significant main effect for sex (P < 0.001) across all visits for Sex FX scores, with the exception of Arousal at Weeks 4, 6, and 8, and Orgasm at Weeks 2, 6, and 8. Where significant differences existed between men and women, women reported lower SF scores. For the IRSD-F total score, a significant difference was also observed across all visits between men and women, with the exception of Week 6. Again, women reported greater levels of sexual dysfunction than men. All further analyses of SF were therefore conducted separately for men and women. Women: Changes in SF During Treatment A 1-way ANOVA revealed significant baseline differences in Sex FX scores among treatment conditions (Sex FX total, P < 0.01; Desire, P < 0.01; Arousal, P < 0.01; overall satisfaction, P < 0.01): women in the paroxetine group reported significantly lower levels of SF than women in the bupropion SR group, on all comparisons. The MMRM analysis of change for Sex FX with visit, treatment, and visit-by-treatment interactions as effects in the model, and with corresponding baseline scores included as covariates, revealed no significant difference by visit, treatment, or visit-by-treatment on total, Desire, Arousal, Orgasm, or overall satisfaction scores on the Sex FX scale (Click to view Table 1). Men: Changes in SF During Treatment There was no statistically significant difference in Sex FX scores between treatment groups for men at baseline (Sex FX, P = 0.50; Desire, P = 0.76; Arousal, P = 0.23; Orgasm, P = 0.96; and overall satisfaction, P = 0.67). The analysis of change for the Sex FX was conducted using the MMRM with visit, treatment, and visit-by-treatment interactions as effects in the model and with corresponding baseline scores as covariates. This revealed a significant treatment effect by visit for Sex FX total (P < 0.001), Desire (P < 0.001), and overall satisfaction (P < 0.01). Paired t tests confirmed that this effect was accounted for by a decrease in SF scores during paroxetine treatment (Sex FX total, P < 0.002; Desire, P < 0.005; Arousal, P < 0.005; and overall satisfaction P < 0.057). The paroxetine group displayed a significant deterioration from baseline to Week 8, on Sex FX total (P < 0.01), Desire (P < 0.01), Arousal (P < 0.05), Orgasm (P < 0.01), and overall satisfaction ( < 0.01) scores, whereas no significant change was observed in any of these measures across visits in men randomized to bupropion SR (Click to view Table 2). Correlation Between Sex FX and the IRSD-F in Men and Women Concurrent validity of the Sex FX scale was evaluated by examining the correlations between Sex FX total and overall satisfaction scores, and the IRSD-F total score. The results of the correlational analysis are presented in Table 3. A statistically significant negative correlation was found for both men and women between the IRSD-F total and Sex FX scores at all visits, reflecting the inverse relation between function on Sex FX and dysfunction on IRSD-F.
Changes in Depression Over Time There was no difference in HDRS17 scores at baseline between bupropion SR (mean 21.8, SD 2.9) and paroxetine (mean 22.2, SD 3.6) groups or between men (mean 22.1, SD 3.1) and women (mean 21.9, SD 3.5). Repeated measures ANOVA indicated a significant reduction over time for both treatment groups (P < 0.01), with no significant difference between treatments or between men and women. Pearson chi-square tests also yielded no significant differences between treatment groups on HDRS17 scores response or in remission rates (Table 4).
Relation Between SF and Depression We computed correlation coefficients separately for men and women to examine the relation between Sex FX and HDRS17 scores. To evaluate the relation between SF scores and responder status (response > 50% reduction in HDRS17 score) as well as remitter status (a score of 7 or less on the HDRS17), we conducted a 1-way ANOVA separately for men and women. For women, there was a significant negative relation across visits between HDRS17 and Sex FX total (Week 0, 2, 4, 6, and 8), Desire (Week 0, 4, 6 and 8) (see Figure 1), Arousal (Week 6), Orgasm (Week 8), and overall satisfaction (Week 0, 2, 4, 6, and 8) scores. There was no significant relation between Sex FX and HDRS17 scores at any visit for men.
We found significant differences between women responders and nonresponders who received paroxetine on Desire (Week 6, P < 0.04), Arousal (Week 4, P < 0.05), and overall satisfaction (Week 6, P > 0.01; Week 8, P < 0.04). Among those who received bupropion, significant differences were observed on Sex FX total (Week 2, P < 0.01; Week 8, P < 0.01) and arousal (Week 2, P < 0.02; Week 8, P < 0.01). We observed significant differences between female remitters and nonremitters in the paroxetine group on Desire (Week 2, P < 0.01) and overall satisfaction (Week 6, P < 0.02; Week 8 P < 0.05). Among those who received bupropion, significant differences were observed on Sex FX total (Week 8, P < 0.01) and desire (Week 2, P < 0.01; Week 8, P < 0.02). There was a significant relation between improved SF and response or remission states. For men, there was only a significant difference between responders and nonresponders on overall satisfaction (Week 6, P < 0.02) in the paroxetine group, and, no significant differences were observed across the Sex FX total and subscale scores between responders and nonresponders in the bupropion group. Significant differences between remitters and nonremitters in the paroxetine group were observed on Sex FX Total (Week 2, P < 0.03; Week 6, P < 0.01; Week 8, P < 0.02), Desire (P < 0.01), Arousal (Week 6 P < 0.01; Week 8, P < 0.01) and overall satisfaction (Week 6, P < 0.01; Week 8, P < 0.01). We observed significant differences on overall satisfaction (Week 6, P < 0.04; Week 8, P < 0.02). In both cases male nonresponders and nonremitters reported worse levels of SF. DiscussionThe Sex FX scale identified differences in scores between men and women with depression prior to antidepressant treatment, and differences between bupropion and paroxetine on reported sexual side effects in men but not in women. Prior to treatment, women reported significantly lower levels of SF than men. Men displayed deterioration in SF during treatment with paroxetine but not during treatment with bupropion SR, whereas there was no change in SF with either drug in women. Men and women also differed in the relation between antidepressant response and SF. Although there was no difference in antidepressant efficacy or response rates to paroxetine or bupropion SR between men and women, there was a direct correlation between change in SF and change in depression in women but not in men. This was true for both paroxetine and bupropion and supports previous reports that effective treatment for depression is more likely to be associated with improved SF in women (5). In men, SF is more likely to be influenced by the type of antidepressant selected rather than treatment response (13,19). To be included in the study, patients were required to have experienced sexual interest and activity within the month prior to the study. This was a clinical trial designed to evaluate improvement or worsening of SF with 2 antidepressant agents. Conversely, it did not allow an examination of depression patients who reported neither sexual interest nor activity prior to antidepressant treatment or an examination of those who might have been sexually interested and active during treatment. The effect of antidepressants on SF appears to be influenced by the extent to which each drug effects serotonin, norepinephrine, and dopamine reuptake inhibition; prolactin release; and inhibition of NO synthetase (20,21). Among commonly prescribed antidepressants, SSRIs are most likely to be associated with impaired SF (22,23). Paroxetine has greater selectivity for serotonin reuptake relative to dopamine reuptake and increased cholinergic receptor blockade. It is also an inhibitor of NO synthetase, which may explain the increased rate of impaired SF, compared with other SSRIs (5, 24). Conversely, bupropion, with a novel mechanism of action involving dual inhibition of norepinephrine and dopamine reuptake, is devoid of any direct effects on the serotonin system (25). There are several limitations to this study. Numerous factors may influence the reporting of SF, including age, relationship status, comorbid illness, concomitant medications, and varying dosages of medication. The diagnosis of MDD and severity of depression, rather than impaired SF, were the primary entry criteria, and this coincidentally resulted in significantly lower baseline Sex FX scores for women in the paroxetine group. Although this study excluded patients with comorbid psychiatric disorders, it is possible that anxiety symptoms may have been unevenly distributed between treatment groups, which may have influenced the distribution of SF among women at baseline. There were roughly equal numbers of men (53%) and women (47%) recruited to the study. While this facilitated statistical comparisons between men and women, it does not reflect the twofold increase in prevalence of MDD among women, compared with men, in the community. Intimacy, stability of relationships, and sexual preference are among the other factors for which we did not control. Although patients were randomized and treated under double-blind conditions, there was no placebo control. We are therefore unable to report the extent to which differences in Sex FX scores between paroxetine and bupropion SR are in excess of a placebo treatment effect. These results support the importance of establishing baseline levels of SF and repeating the assessments systematically over the course of treatment (9,26,15). The study also suggests that men and women with depression differ in SF before starting antidepressant therapy and are affected differently in terms of SF during treatment. Future studies designed to compare the effects on SF of different antidepressant or other psychotropic drugs need to take these factors into account. Funding and SupportFunding was provided by Boehringer Ingelheim, Canada. AcknowledgmentsThis study was completed across 15 Canadian sites. The following principal investigators contributed to recruitment: John Angel, St Johns, Newfoundland; Pierre Assalian, Montreal General Hospital, Montreal, Quebec; Vern Bennett, MD, Royal University Hospital, Saskatoon, Saskatchewan; Pierre Chue, Psychopharmacology Research Unit, Alberta; David Johnston, Calgary General Hospital, Peter Louhgeed Centre, Calgary, Alberta; Hanumantha Koka, Sudbury Algoma Hospital Network North, Sudbury, Ontario; Stanley Kutcher, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; Raymond Lam, MD, University of British Columbia, Mood Disorders Clinic, Vancouver, British Columbia; Daniel Lefcoe, London Health Sciences Centre, London, Ontario; Lee Rasmusen, Inova Health Research, Kelowna, British Columbia; Arun Ravindran, The Royal Ottawa Health Care Group, Royal Ottawa Hospital, Ottawa, Ontario; Amarendra Singh, Kingston Psychiatric Hospital, Kingston, Ontario; Meir Steiner, St. Joseph’s Hospital, Hamilton, Ontario; and Pierre Vincent, and Robert Giffard, Quebec City, Quebec. The authors would also like to extend appreciation to Claire O’Donovan, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia and Beata Eisfeld, University Health Network, Toronto, Ontario, for comments on an earlier version of the manuscript. References1. Casper RC, Redmond DE Jr, Katz MM, Schaffer CB, Davis JM, Koslow SH. Somatic symptoms in primary affective disorders: presence and relationship to the classification of depression. Arch Gen Psychiatry 1985;42:1098–1104. 2. Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM. Sexual Dysfunction before antidepressant therapy in major depression. J Affect Disord 1999;56:201–208. 3. McIntyre RS, Kennedy SH, Bagby RM, Bakish D. Assessing full remission. J Psychiatry Neurosci 2002;27:235–39. 4. Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C, Bass KI, and others. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002;63:357–66. 5. Kennedy SH, Eisfeld BS, Dickens SE Bacchioci JR, Bagby RM. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 2000;61:276–81. 6. Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM. Antidepressant-induced sexual dysfunction. Ann Pharmocother 2002;36:1577–9. 7. Labbate LA, Croft HA, Oleshansky MA. Antidepressant-related erectile dysfunction: management via avoidance, switching antidepressants, antidotes, and adaptation. J Clin Psychiatry 2003;64:11–9. 8. Montejo AL, Llorca G, Izquierdo JA, Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry 2001;62(Suppl 3):10–21. 9. Rivas-Vazquez RA, Rey GJ, Blais MA. SD associated with antidepressant treatment. Professional Psychology: Research and Practice 2000;31:641–51. 10. Segraves RT, Kavoussi R, Hughes AR, Batey SR, Johnston JA, Donahue R, and others. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol 2000;20:122–8. 11. Zajecka J, Dunner DL, Gelenberg AJ,Hirschfeld RM, Kornstein SG, Ninan PT, and others. Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, psychotherapy, and their combination. J Clin Psychiatry 2002;63:709–16. 12. Kennedy SH, Fulton KA, Rasmussen JGC. Sex FX: estimation of normative values and comparison with values from patients with major depressive disorder. Vancouver (BC): Canadian Psychiatric Association; 2005. 13. Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, and others. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002;63:181–6. 14. Croft H, Settle E Jr, Houser T. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther 1999;21:643–8. 15. Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA.15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7(3):106–13. 16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. 17. Canadian Pharmacists Association. The compendium of pharmaceuticals and specialties. Ottawa (ON): Canadian Pharmacist Association; 2004. 18. Mallinckrodt CH, Sanger TM, Dube S, DeBrota DJ, Molenberghs G, Carroll RJ, and others. Assessing and interpreting treatment effects in longitudinal clinical trials with missing data. Biol Psychiatry 2003;53:754–60. 19. Piazza LA, Markowitz JC, Kocsis JH and others. Sexual functioning in chronically depressed patients treated with SSRI antidepressants: A pilot study. Am J Psychiatry 1997;154:1757–9. 20. Pomerantz SM, Hepner BC, Wertz JM. 5-HTIA and 5-HT IC/ID receptor agonists produce reciprocal effects on male behaviour of rhesus monkeys. Eur J Pharmacol 1983;243:227–34. 21. Pollack MH, Reiter S, Hammerness P. Genitourinary and sexual adverse effects of psychotropic medication. Int J Psychiatry Med 1992;22:305–27. 22. Rosen R, Lane RM, Menza M. Effects of SSRI on sexual function: a critical review. J Clin Psychopharmacol 1999;19:67–85. 23. Weiner DN, Rosen RC. Medications and their impact on sexual function. In: Sipski ML, Alexander CJ, editors. Sexual function in people with disability and chronic illness. Gaithersburg (MD): Aspen Publishers; 1997. p 85–118. 24. Montego-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, and others. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23:176–94. 25. Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the neuropharmcology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry 2004;6:159–65. 26. Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced SD. J Affect Disord 2002;69:119–40. Author(s)Manuscript received March 2005, revised, and accepted August 2005. 1. Professor of Psychiatry, University of Toronto, Toronto, Ontario; Psychiatrist-in-Chief, University Health Network, Toronto, Ontario 2. Clinical Research Coordinator, University Health Network, Toronto, Ontario. 3. Professor of Psychiatry, University of Toronto, Toronto, Ontario; Director, Clinical Research Department, Centre for Addiction and Mental Health, Toronto, Ontario. 4. Research Assistant, University Health Network, Toronto, Ontario. 5. PhD Candidate, York University, Toronto, Ontario. 6. Research Analyst, University Health Network, Toronto, Ontario. Address for correspondence: Dr SH Kennedy, University Health Network, 200 Elizabeth Street, 8 Eaton North Suite 222 , Toronto, ON M5G 2C4 e-mail: sidney.kennedy@uhn.on.ca
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